ABSTRACT One of the great unsolved mysteries regarding neurobiology of mood disorders is - why do some patients suffer only from episodes of depression (unipolar depression or UD, also known as major depression) while others suffer from episodes of both depression and the opposite mood state of mania (bipolar disorder or BD). In the clinical setting, both UD and BD depression (BDD) are difficult to differentiate and can only be teased apart by obtaining a detailed longitudinal history to identify periods of (hypo)mania. However, in young patients, early in the course of the illness, this history is either very difficult to elicit or not present because the first few episodes of BD are usually of depression. Only with time, and usually after years of misdiagnosis and inappropriate treatment, a proportion of the depressed subjects start suffering from episodes of overt (hypo)mania and reveal themselves to be actually suffering from BD. Therefore, there is a critical need to identify, particularly in young patients, neurobiological differences between BDD and UD as well as differences between UD patients at a high risk for developing BD (HRUD) and UD patients with low risk of developing BD (LRUD). The investigators have been conducting functional magnetic resonance imaging (fMRI) studies of corticolimbic connectivity and activity for nearly a decade and in recent studies have identified resting state connectivity abnormalities as well as task-induced activation abnormalities in BD and UD. Preliminary data suggests that these measures may be helpful in differentiating between BDD and UD. This proposal will investigate corticoamygdalar connectivity and activation abnormalities in 40 BDD, 80 UD (40 HRUD and 40 LRUD) young adult patients (21 - 35 yrs of age) compared to 40 matched healthy controls (HC). Besides investigating cross-sectional differences between groups, an exploratory prospective validation of the BDD related abnormalities would also be conducted by treating the 80 UD subjects with antidepressants for 6 months and then following them up naturalistically for another 18 months. Subjects will be assessed frequently for emergence of (hypo)mania to be identified as converters to a BD diagnosis. Differences between converters and non-converters on the imaging measures will be investigated and an analysis will be conducted whether the imaging measures correlate with risk of conversion over time. Innovative aspects of this proposal are: it addresses the understudied area of differences between unmedicated BDD and UD patients using fMRI measures to study circuit level abnormalities; studies young adults in which the issue is most important; investigates (in line with aims of the new NIMH Research Domain Criteria (RDoC) project) the similarities between HRUD and BDD subjects; and uses a cross-sectional as well as prospective study design to explore the power of the imaging measures to predict the risk of conversion from UD to BD diagnosis. Findings from this study will have a critical impact both on the understanding of the neurobiology of mood disorders as well as on the difficult clinical issue of how to differentiate between BDD and UD patients in young adults.